Estrogen has multiple salutary neuromodulatory, neurotrophic, and neuroprotective properties. These salutary effects are presumable mediated through the estrogen receptors that are widely, but selectively distributed throughout the brain. In particular, estrogen receptors are densely populated in the neocortex, hippocampus, amygdala, and basal forebrain; areas of the brain that afflicted by Alzheimer's disease (AD) and underlie specific cognitive functions impaired in patients with AD. Moreover, these cognition-mediating regions of the brain demonstrate neurotrophic activity in response to estrogen release. Preliminary evidence from clinical studies indicates that administration of estrogen improves memory in postmenopausal women with AD. In addition, results of epidemiological studies suggest that estrogen therapy might reduce the risk of developing AD. However, several issues of critical clinical significance need to be further evaluated before the potential role of estrogen for the treatment of AD can be firmly established. These issues include the following: 1) whether the cognition- enhancing actions of estrogen are dose-dependent and persist over an extended period of administration, 2) if the salutary effects of estrogen on cognitive function will effectively translate into improved skills of independent living, 3) whether the potential beneficial effects on cognition and physical function will persist when estrogen is co-administered with a progestin over both short and extended periods, and finally, 4) whether ApoE genotype influences the therapeutic response of an individual to treatment with estrogen. The proposed randomized, double-blind, placebo-controlled, parallel-group design clinical study will evaluate the dose-dependent effects of prolonged administration of both unopposed and opposed (i.e., with a progestin) estrogen on cognitive function and skills of independent living in postmenopausal women with AD.
| Gleason, C E; Cholerton, B; Carlsson, C M et al. (2005) Neuroprotective effects of female sex steroids in humans: current controversies and future directions. Cell Mol Life Sci 62:299-312 |
| Cholerton, Brenna; Gleason, Carey E; Baker, Laura D et al. (2002) Estrogen and Alzheimer's disease: the story so far. Drugs Aging 19:405-27 |
